Simona Pagliuca, Jarl Eduard Mooyaart, Francis Ayuketang Ayuk, Robert Zeiser, Victoria Potter, Peter Dreger, Wolfgang Andreas Bethge, Inken Hilgendorf, David Michonneau, Alessandro Rambaldi, Henrik Sengeloev, Jakob R Passweg, Deborah Susan Richardson, Tobias Gedde-Dahl, Francesca A M Kinsella, Matthias Edinger, Stephan Mielke, Matthias Eder, Marco Andreani, Pietro Crivello, Pietro Merli, Jorinde Desiree Hoogenboom, Liesbeth C de Wreede, Christian Chabannon, Jürgen Kuball, Carmelo Gurnari, Katharina Fleischhauer, Annalisa Ruggeri, Tobias Lenz
Allogeneic hematopoietic cell transplantation (allo-HCT) hinges on a delicate trade-off between graft-versus-tumor control and graft-versus-host disease (GvHD), mediated by donor T-cell recognition of antigens presented by recipient human leukocyte antigen (HLA) molecules. We hypothesized that, beyond allele-level matching, sequence divergence at peptide-binding grooves across donor and recipient HLA loci shapes these responses. To this end, we evaluated the effect of HLA evolutionary divergence (HED), a metric quantifying amino acid variability at HLA peptide-binding sites, on selected hematological malignancies in 4,695 patients undergoing allo-HCT from a 9/10 mismatched unrelated donor (MMUD), reported to the EBMT database. We examined (i) locus-specific recipient HED (HED-R) and (ii) "HED-mismatch" (HED-MM), capturing immunopeptidome divergence at the mismatched locus. While dichotomous mismatch status explained differences in survival and acute GvHD risk (with overall greater detriment for class I loci), HED metrics uncovered substantial within-mismatch heterogeneity. In DRB1 mismatched subgroup, HED-MM at this locus, independently predicted inferior relapse-free survival (RFS) with an attenuating time-dependent association, further modulated by cross-locus HED-R. In this subgroup, higher HED-R at HLA-A and HLA-C associated with increased risks of acute GvHD and non-relapse mortality, respectively. Among HLA-B-mismatched pairs, higher DRB1 HED-R associated with worse overall survival (OS) and RFS and higher relapse risk. In the HLA-A-mismatched subgroup, higher HED-R at HLA-A increased chronic GvHD risk. Collectively, HED-derived metrics complement conventional mismatch classification by capturing qualitative differences in donor-recipient immunopeptidome interactions and reveal a complex, non-linear interplay among alleles across mismatch subgroups that modulates the clinical impact of mismatching.